Abstract
Actin filaments, with their associated tropomyosin polymers, and microtubules are dynamic cytoskeletal systems regulating numerous cell functions. While antimicrotubule drugs are well-established, antiactin drugs have been more elusive. We previously targeted actin in cancer cells by inhibiting the function of a tropomyosin isoform enriched in cancer cells, Tpm3.1, using a first-in-class compound, TR100. Here, we screened over 200 other antitropomyosin analogues for anticancer and on-target activity using a series of in vitro cell-based and biochemical assays. ATM-3507 was selected as the new lead based on its ability to disable Tpm3.1-containing filaments, its cytotoxicity potency, and more favorable drug-like characteristics. We tested ATM-3507 and TR100 alone and in combination with antimicrotubule agents against neuroblastoma models in vitro and in vivo Both ATM-3507 and TR100 showed a high degree of synergy in vitro with vinca alkaloid and taxane antimicrotubule agents. In vivo, combination-treated animals bearing human neuroblastoma xenografts treated with antitropomyosin combined with vincristine showed minimal weight loss, a significant and profound regression of tumor growth and improved survival compared with control and either drug alone. Antitropomyosin combined with vincristine resulted in G2-M phase arrest, disruption of mitotic spindle formation, and cellular apoptosis. Our data suggest that small molecules targeting the actin cytoskeleton via tropomyosin sensitize cancer cells to antimicrotubule agents and are tolerated together in vivo This combination warrants further study. Mol Cancer Ther; 16(8); 1555-65. ©2017 AACR.
Highlights
High-risk neuroblastoma is responsible for 10%–15% of pediatric cancer mortality
ATM-3507 retains the three core structural components of TR100, namely an indole scaffold and two binding arms: [1] the "polar arm," which terminates in an ionizable nitrogen atom, and [2] the "nonpolar arm," which is predominantly hydrophobic in nature (Fig. 1 A and B)
While TR100 binds close to the C-terminus of the tropomyosin dimer, the modified nonpolar arm of ATM-3507 is able to make better contact with the helices of the tropomyosin dimer, reaching toward the center of the dimer and interacting with side chains specific for the Tpm3.1 tropomyosin isoform
Summary
High-risk neuroblastoma is responsible for 10%–15% of pediatric cancer mortality. Vinca alkaloids, such as vincristine, which disrupt assembly of tubulin monomers into microtubules, are foundational in chemotherapeutic regimens used to treat patients with neuroblastoma. Ment with chemotherapy, surgery, radiation, high-dose chemotherapy with autologous stem cell rescue, anti-GD2 immunotherapy, and retinoic acid, about 50% of children with high-risk neuroblastoma experience disease relapse. Children with relapsed/refractory neuroblastoma have a
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
